DCIR is endocytosed into human dendritic cells and inhibits TLR8-mediated cytokine production

C-type lectin receptors (CLRs) expressed on APCs play a pivotal role in the immune system as pattern-recognition and antigen-uptake receptors. In addition, they may signal directly, leading to cytokine production and immune modulation. To this end, some CLRs, like dectin-l and dendritic cell immunoreceptor (DCIR), contain in-tracellular ITIMs or ITAMs. In this study, we explored expression and function of the ITIM-con-taining CLR DCIR on professional APCs. DCIR is expressed on immature and mature monocyte-de-rived DCs (moDC) but also on monocytes, macro-phages, B cells, and freshly isolated myeloid and plasmacytoid DCs. We show that endogenous DCIR is internalized efficiently into human moDC after triggering with DCIR-specific mAb. DCIR in-ternalization is clathrin-dependent and leads to its localization in the endo-/lysosomal compartment, including lysosome-associated membrane pro- tein-1+ lysosomes. DCIR triggering affected neither TLR4- nor TLR8-mediated CD80 and CD86 up-regulation. Interestingly, it did inhibit TLR8-mediated IL-12 and TNF-α production significantly, and TLR2-, TLR3-, or TLR4-induced cy- tokine production was not affected. Collectively, the data presented characterize DCIR as an APC receptor that is endocytosed efficiently in a clathrin-dependent manner and negatively affects TLR8-mediated cytokine production. These data provide further support to the concept of CLR/ TLR cross-talk in modulating immune responses. copy; Society for Leukocyte Biology.